Patch

ABSTRACT

A patch having good transdermal property which utilizes a suppository base e.g. triglyceride of a vegetable saturated fatty acid having 12 to 18 carbon atoms together with a penetration enhancer.

This is a continuation of application Ser. No. 17,886, filed Feb. 20,1987, now abandoned, which is a continuation of application Ser. No.699,585, filed Feb. 8, 1985.

FIELD OF THE INVENTION

This invention relates to a patch and more particularly to a patchshowing an increased skin penetration rate of drug and an increased drugreleasing rate.

BACKGROUND OF THE INVENTION

A patch is one form of transdermal formulations whose application forsystemic therapy is recently in the limelight and has hitherto beenapplied to nitroglycerin, scopolamine, etc.

Among these patches, the patches known as the patch of nitroglycerin areone containing a crosslinked silicon polymer as a base, one containing aviscous silicone liquid as a base together with multi-pore membrane forcontrolled release of drug, and one containing a matrix composed ofpolyvinyl alcohol, polyvinyl pyrrolidone, and glycerol as a base. Also,the patch of scopolamine contains a mixture of high molecularpolyisobutene, low molecular polyisobutene, and a mineral oil as a base.

SUMMARY OF THE INVENTION

On the other hand, this invention provides a patch having goodtransdermal property by using a suppository base which has never beenused as a base for patches, that is by using fats and oils mainlycomposed of cacao butter, isocacao butter, or triglyceride of avegetable saturated fatty acid having 12 to 18 carbon atoms as a basetogether with a penetration enhancer.

Among these bases, cacao butter and isocacao butter are naturalvegetable saturated fatty acid triglycerides and the latter fats andoils, i. e., the fats and oils composed of the triglyceride of avegetable saturated fatty acid of 12 to 18 carbon atoms aresemi-synthesized ones. The latter fats and oils are composed of thetriglyceride of a vegetable satruated fatty acid such as lauric acid (C12), myristic acid (C 14), palmitic acid (C 16), and stearic acid (C 18)or a mixture of these triglycerides. They are commercially available asthe trade name of "Witepsol" (made by Dinamit Nobel Co.) and can be usedas fats and oils for the base in this invention. Suitable commerciallyavailable fats and oils are Witepsol H-5, Witepsol H-15, etc.

Thus, according to this invention, there is provided a patch comprisinga solution or suspension of a drug component uniformly dispersed in abase mainly comprising a penetration enhancer and fats and oils composedof cacao butter, isocacao butter or the triglyceride of a vegetablesaturated fatty acid having 12 to 18 carbon atoms.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1(a) is a plane view showing an example of the construction of apatch of this invention,

FIG. 1(b) is a cross sectional view thereof, and

FIG. 2 is a cross sectional view showing another embodiment of theconstruction of a patch of this invention.

DESCRIPTION OF THE PREFERRED EMBODIMENT

Now, as the drug component for the patches of this invention,nicardipine hydrochloride, nifedipine, dipyridamole, formoterolfumarate, indenolol, γ-oryzanol, digoxin, β-methyldigoxin, dimemorfanphosphate, propranolol, etc., can be used. These drug components havehitherto been supplied for treatment as formulations for oraladministration and the invention first makes possible the percutaneousadministration of these drugs. Bioavailability of drug applied to skinusually is pretty low and hence systemic transdermal formulations areutilized only for limited drugs. Also, since transdermal formulationsare used by affixing to the skin, there are restrictions about the kindsand addition amounts of a base to be used and additional component orcomponents from a view point of the maintenance of the form.

The solvent for dissolving or suspending a drug component in thisinvention, a solvent which can be easily released from the oily base andis compatible with water is fundamentally suitable and examples of thesolvent are lactic acid, benzyl alcohol, N-methyl-2-pyrrolidone,crotamiton, glycols (e. g., propylene glycol, ethylene glycol, etc.,),alcohols (e. g., ethanol, isopropanol, etc.,), etc. These solvents maybe selectively used solely or as a mixture of them. embodiment of theconstruction of a patch of this invention.

DESCRIPTION OF THE PREFERRED EMBODIMENT

Now, as the drug component for the patches of this invention,nicardipine hydrochloride, nifedipine, dipyridamole, formoterolfumarate, indenolol, γ-oryzanol, digoxin, β-methyldigoxin, dimemorfanphosphate, propranolol, etc., can be used. These drug components havehitherto been supplied for treatment as formulations for oraladministration and the invention first makes possible the percutaneousadministration of these drugs. Bioavailability of drug applied to skinusually is pretty low and hence systemic transdermal formulations areutilized only for limited drugs. Also, since transdermal formulationsare used by stiking on the skin, there are restrictions about the kindsand addition amounts of a base to be used and additional component orcomponents from a view point of the maintenance of the form.

The solvent for dissolving or suspending a drug component in thisinvention, a solvent and can be easily released from the oily base andis compatible with water is fundamentally suitable and examples of thesolvent are lactic acid, benzyl alcohol, N-methyl-2-pyrrolidone,crotamiton, glycols (e. g., propylene glycol, ethylene glycol, etc.,),alcohols (e. g., ethanol, isopropanol, etc.,), etc. These solvents maybe selectively used solely or as a mixture of them.

These solvents are properly selected according to characteristics of thedrug component. That is, in the case of using nicardipine hydrochloride,an aqueous urea solution, lactic acid, ethanol, propylene glycol, benzylalcohol, etc., are properly used as a mixture of them and particularlysuitable solvents are a mixed solvent of an aqueous urea solution andlactic acid or propylene glycol and a mixed solvent of an aqueous ureasolution, benzyl alcohol, and propylene glycol. Also, a mixed solventof, for example, N-methyl-2-pyrrolidone and propylene glycol is suitablyused for nifedipine, a mixed solvent of, for example, lactic acid,propylene glycol, and an aqueous urea solution for dipyridamole, a mixedsolvent of, for example, ethylene glycol and propylene glycol forformoterol fumarate, a solvent such as N-methyl-2-pyrrolidone forγ-oryzanol, and a solvent such as ethylene glycol and propylene glycolfor indenolol.

The amount of the solvent for use is the minimum amount capable ofdissolving or suspending the drug component and maintaining the form ofpatch.

As the penetration enhancer, urea, diisopropyl adipate, diethyl adipate,diethyl sebacate, isopropyl myristate, isopropyl palmitate, middle chainfatty acid glyceride, sorbitan middle chain fatty acid ester, etc., canbe used. These penetration enhancers can be used solely or as acombination of them. In addition, since propylene glycol which is usedas the solvent has also a penetration enhancing action, theabove-described penetration enhancer is not necessarily required when itis used as the solvent.

The patches of this invention may further contain, in addition to theabove-described components, emulsifiers (e. g., a glycerol monostearicacid ester (Nikkol MGS-B, trade name), polyoxyethylene-hardened castoroil (Nikkol HCO-60, trade name), etc.,), hardening agents (e. g., higheralcohols such as cetyl alcohol, etc.,), oily ointment bases (e. g.,white petrolatum etc.,), suspending agents (e. g., silicic anhydride(Aerosil, trade name), etc.,), etc., but fundamentally, the base of anamount capable of maintaining the solid state as the patch form atnormal temperature is used.

It is preferred that the patch of this invention is prepared by kneadinga solution of drug and the base. That is, the base is melted at atemperature (about 40° C.) necessary for melting the base, a drugsolution is gradually added to the molten base while kneading the moltenbase, and the resultant mixture is kneaded and solidified to provide thepatch.

The proportion of each of the patch components of this invention issuitably selected and the amount of the drug component is usuallyproperly determined according to the nature thereof. Also, in general,the amount of the solvent is the smallest necessary amount capable ofdissolving or suspending the drug component. The proportion of the baseis 60 to 85 w/w %, the proportion of the penetration enhancer is 0.5 to20 w/w %, preferably 5 to 15 w/w %, and the proportion of othercomponent or components (e. g., an emulsifier, a suspending agent, apreservative, etc.,) is 0.5 to 10 w/w %.

The patch of this invention can be very easily prepared as compared withthe above-described conventional patches. Also, the base of the patch ofthis invention is melted at about body temperature, the patch of thisinvention is excellent in percutaneous absorption.

The construction of the patch of this invention is almost the same asthose of conventional patches. FIG. 1 shows a fundamental structure ofan example of the patch of this invention, that is, FIG. 1(a) is a planeview showing the construction of an example of the patch of thisinvention and FIG. 1(b) is a cross sectional view of it. As shown inFIG. 1, patch components 2 are packed in a polyvinyl chloride container1, an adhesive layer 3 is formed at the portion to be applied to theskin, and the surface of the adhesive layer 3 is covered by a liner 4.

The patch of this invention has the above-described advantages but asanother embodiment of the preferred patch of this invention, there is apatch further having a heating element and a filter paper impregnatedwith propylene glycol. That is, for further improving theform-maintaining property, the patch of this invention sometimescontains a hardening agent such as a higher alcohol (e. g., cetylalcohol, stearyl alcohol, etc.,), solid paraffin, microcrystalline wax,etc. In this case, however, the melting point range of the patch isliable to become broader and it sometimes happens that the patch doesnot melt sharply by the body temperature alone. In such a case, thesystem, as shown in FIG. 2, that a concaved portion is formed at theouter portion (the opposite side to the side to be applied to the skin)of the patch and a heating element 5 is disposed in the concaved portionfor heating the patch at the application thereof to the skin can beemployed.

For the heating element, a composition mainly composed of an iron powderand generating heat in the presence of oxygen and water is used. Theupper portion of the heating element is covered by an aluminum seal 6,etc., and the cover is peeled off prior to use. Also, a propyleneglycol-impregnated filter paper 7, for example, Toyo Filter Paper No. 7(trade name) preliminary impregnated with propylene glycol is disposedbetween the patch component 2 and a liner 4. By the foregoingconstruction, the solution of drug dispersed in the oily base of thepatch is attracted to the filter paper side at use, whereby theoccurence of the molten liquid is prevented and all the surface area ofthe patch can be effectively utilized.

The following examples will still further illustrate this invention.

EXAMPLE 1

A mixture of 150.5 g of Witepsol H-15 and 5 g of Nikkol MGS-B was meltedat about 60° C. and after cooling to about 45° C., the mixture wastransferred into a kneader. A solution of 4.5 g of nicardipinehydrochloride dissolved in 40 g of a mixture of benzyl alcohol/propyleneglycol/aqueous 50% urea solution (1:1:2, ww) was gradually added to themixture and the resultant mixture was kneaded. Then, the mixture wasfilled in a plastic container made by polyvinyl chloride and solidifiedby cooling to provide a patch.

EXAMPLE 2

By following the same procedure as Example 1 using Witepsol H-5 in placeof Witepsol H-15, a patch was obtained.

EXAMPLE 3

A mixture of 159.1 g of Witepsol H-5 and 9.1 g of Nikkol MGS-B wasmelted at about 60° C. and after cooling to about 45° C., the mixturewas transferred into a kneader. Then, a solution of 4.5 g of nicardipinehydrochloride dissolved in 27.3 g of a mixture of lactic acid/aqueous50% urea solution (1:2 w/w) was gradually added to the mixture and theresultant mixture was kneaded. The mixture was filled in a plasticcontainer of polyvinyl chloride and solidified by cooling to provide apatch.

EXAMPLE 4

A mixture of 146.4 g of Witepsol H-5 and 9.1 g of Nikkol MGS-B wasmelted at about 60° C. and after cooling to about 45° C., the mixturewas transferred into a kneader. Then, a solution of 4.5 g of nicardipinehydrochloride dissolved in 40 g of a mixture of lactic acid/propyleneglycol/aqueous 50% urea solution (1:1:2 w/w) was gradually added to themixture and the resultant mixture was kneaded. The mixture was filled ina plastic container of polyvinyl chloride and solidified by cooling toprovide a patch.

EXAMPLE 5

A mixture of 115.5 g of Witepsol H-5, 10 g of Nikkol MGS-B, 10 g ofNikkol TS-10 (polyoxyethylene sorbitan monostearate), 10 g of Kalcol 60(trade name, made by Kao Atlas Co., palmityl alcohol) and 10 g ofisopropyl myristate was melted at about 60° C. and after cooling toabout 45° C., the molten mixture was transferred into a kneader.Thereafter, a solution of 4.5 g of nicardipine hydrochloride dissolvedin 40 g of a mixture of benzyl alcohol/propylene glycol/aqueous 50% ureasolution (1:1:2 w/w) was gradually added to the mixture and theresultant mixture was kneaded. The mixture was filled in a plasticcontainer of polyvinyl chloride and solidified by cooling to provide apatch.

EXAMPLE 6

A heating element was equipped to the patch in Example 5. As the heatingelement, Panakairo 25 (trade name, made by Atlas Shoji K. K.) which iscomposed of iron powder (main component), activated carbon, sodiumchloride, etc., was used.

EXAMPLE 7

A mixture of 155 g of Witepsol H-15 and 10 g of Nikkol HCO-60 was meltedat about 50° C. and after cooling to about 45° C., the molten mixturewas transferred into a kneader. Then, a solution of 5 g of nifedipinedissolved in a mixture of 10 g of N-methyl-2-pyrrolidone, 10 g ofpropylene glycol, and 10 g of diisopropyl adipate was gradually added tothe mixture and the resultant mixture was kneaded. The mixture wasfilled in a plastic container of polyvinyl chloride and solidified bycooling to provide a patch.

EXAMPLE 8

A mixture of 148.65 g of Witepsol H-5 and 9.1 g of Nikkol MGS-B wasmelted at about 60° C. and after cooling to about 45° C., the moltenmixture was transferred into a kneader. Then, a solution of 2.25 g ofdipyridamole dissolved in 40 g of a mixture of latic acid/propyleneglycol/aqueous 50% urea solution (1:1:2 w/w) was gradually added to themixture and the resultant mixture was kneaded. The mixture was filled ina plastic container of polyvinyl chloride and solidified by cooling toprovide a patch.

EXAMPLE 9

A mixture of 160 g of Witepsol H-15 and 10 g of Nikkol MGS-B was meltedat about 60° C. and after cooling to about 45° C., the molten mixturewas transferred into a kneader. Then, a solution of 10 mg of formoterolfumarate dissolved in 30 g of a mixture of ethylene glycol/aqueous 50%urea solution (1:2 w/w) was gradually added to the mixture and theresultant mixture was kneaded. The mixture was filled in a plasticcontainer of polyvinyl chloride and solidified by cooling to provide apatch.

EXAMPLE 10

A mixture of 157.5 g of Witepsol H-15 and 10 g of Nikkol MGS-B wasmelted at about 60° C. and after cooling to about 45° C., the moltenmixture was transferred into a kneader. Then, a solution of 2.5 g ofindenolol dissolved in 30 g of a mixture of ethylene glycol/aqueous 50%urea solution (1:2 w/w) was gradually added to the mixture and theresultant mixture was kneaded. The mixture was treated as Example 9 toprovide a patch.

EXAMPLE 11

A mixture of 165 g of Witepsol H-5 and 10 g of Nikkol MGS-B was meltedat about 60° C. and after cooling to about 45° C., the molten mixturewas transferred into a kneader. Then, a solution of 5 g of γ-oryzanoldissolved in 20 g of a mixture of N-methyl-2-pyrrollidone/diisopropyladipate (1:1 w/w) was gradually added to the solution and the resultantmixture was kneaded. Then, the mixture was treated as Example 10 toprovide a patch.

Reference Example

A mixture of 155.5 g of Witepsol H-5, 10 g of Nikkol MGS-B, 10 g ofNikkol IPM (isopropyl myristate), 10 g of Nikkol TS-10 and 10 g ofKalcol 60 was melted and after cooling to about 45° C., the mixture wastransferred into a kneader. Then, 4.5 g of nicardipine hydrochloride wasadded to the mixture followed by kneading and the mixture thus obtainedwas filled in a plastic container of polyvinyl chloride and solidifiedto provide a patch.

Percutaneous absorption test in guinea pig

One patch (about 3 g) packed in the plastic container obtained inExample 3, 4, 5 or 6 or Reference Example was applied to the back skinof a guinea pig shaved at the preceding day and five-fold gauzescircularly punched at the center adapting the outer diameter of theplastic container were placed around the plastic container of the patch.The upper surface of the patch thus surrounded by the gauzes was coveredby Parafilm and further they were fixed by a surgical tape. After 5hours since the application of the patch, the blood was collected andthe concentration of nicardipine hydrochloride in plasma was measuredaccording to the Higuchi et als' method (Journal of Chromatography, 110,301(1975)). The results thus obtained are shown in the following table.

    ______________________________________                                                    Concentration of nicardipine                                      Patch       hydrochloride in plasma                                           ______________________________________                                        Example 3   54.0 ng/ml                                                        Example 4   60.7 ng/ml                                                        Example 5   30.6 ng/ml                                                        Example 6   51.5 ng/ml                                                        Reference    5.6 ng/ml                                                        Example                                                                       ______________________________________                                    

What is claimed is:
 1. A transdermal patch comprised of a polyvinylchloride container, an adhesive layer on said container at the portionto be applied to the skin, and wherein said adhesive layer is covered bya liner, said patch containing a solution or a suspension of a drugcomponent selected from the group consisting of nicardipinehydrochloride, nifedipine, dipyridamole, formoterol fumarate, indenololand -oryzanol, and wherein said drug component is uniformly dispersed ina base mainly comprising cacao butter, isocacao butter or a triglycerideof a vegetable saturated fatty acid having 12 to 18 carbon atomstogether with a penetration enhancer.
 2. The patch as claimed in claim1, wherein the base is fats and oils comprising a triglyceride of avegetable saturated fatty acid having 12 to 18 carbon atoms.
 3. Thepatch as claimed in claim 1, wherein the solution of the drug componentis a solution of nicardipine hydrochloride dissolved in a mixed solventof an aqueous urea solution, lactic acid and propylene glycol.
 4. Thepatch as claimed in claim 1, wherein the solution of the drug componentis a solution of dipyridamole dissolved in a mixed solvent of an aqueousurea solution, lactic acid and propylene glycol.
 5. The patch as claimedin claim 1, wherein the solution of the drug component is a solution ofnicardipine hydrochloride dissolved in a mixed solvent of an aqueousurea solution, benzyl alcohol, and propylene glycol.
 6. The patch asclaimed in claim 1, 4, 5 or 6, wherein a propylene glycol-impregnatedfilter paper is disposed at the side of the patch to be applied to theskin.
 7. A transdermal patch comprised of a container, an adhesive layeron said container at the portion to be applied to the skin, and saidcontainer and surface of the adhesive layer covered by a liner andcontained within said container a solution or a suspension of a drugcomponent selected from the group consisting of nicardipinehydrochloride, nifedipine, dipyridamole, formoterol fumarate, indenololand γ-oryzanol, and wherein said drug component is uniformly dispersedin a base mainly comprising cacao butter, isocacao butter or atriglyceride of a vegetable saturated fatty acid having 12 to 18 carbonatoms together with a penetration enhancer.